Cardiac protection by mitoKATP channels is dependent on Akt translocation from cytosol to mitochondria during late preconditioning

2006 ◽  
Vol 290 (6) ◽  
pp. H2402-H2408 ◽  
Author(s):  
Nauman Ahmad ◽  
Yigang Wang ◽  
Khawaja Husnain Haider ◽  
Boyu Wang ◽  
Zeeshan Pasha ◽  
...  
Keyword(s):  
Cardiac Tissue ◽  
Diastolic Pressure ◽  
Left Ventricular ◽  
Phosphatidylinositol 3 Kinase ◽  
Akt Phosphorylation ◽  
Beneficial Effects ◽  
Late Preconditioning ◽  
Phosphorylated Akt ◽  
Developed Pressure ◽  
Mitokatp Channels

This investigation elucidates the Akt/mitochondrial ATP-sensitive K+ (mitoKATP) channel signaling pathway in late pharmacological preconditioning, using the mitoKATP channel openers BMS-191095 (BMS) and diazoxide (DE). BMS (1 mg/kg ip) and DE (7 mg/kg ip) alone or BMS plus wortmannin (WTN, 15 μg/kg ip), an inhibitor of phosphatidylinositol 3-kinase, and BMS plus 5-hydroxydecanoic acid (5-HD, 5 mg/kg ip), an inhibitor of mitoKATP channels, were administered to male mice. Twenty-four hours later, hearts were isolated and subjected to 40 min of ischemia and 120 min of reperfusion via Langendorff's apparatus. Both BMS and DE reduced left ventricular end-diastolic pressure and increased left ventricular developed pressure as well as reduced LDH release. Coadministration of BMS and WTN abolished the beneficial effects of BMS on cardiac function. Moreover, BMS and DE accelerated Akt phosphorylation in cardiac tissue as determined by Western blot analysis and also significantly reduced apoptosis compared with ischemic control. WTN significantly suppressed BMS-induced Akt phosphorylation, whereas 5-HD had no effect on Akt phosphorylation in cytosol, and the effect of BMS on apoptosis was abolished. It is concluded that the cardioprotective effect by mitoKATP channels is attributed to the translocation of phosphorylated Akt from cytosol to mitochondria.

Effect of preconditioning on ryanodine-sensitive Ca2+ release from sarcoplasmic reticulum of rat heart

1996 ◽  
Vol 271 (3) ◽  
pp. H876-H881 ◽  
Author(s):  
M. Tani ◽  
Y. Asakura ◽  
H. Hasegawa ◽  
K. Shinmura ◽  
Y. Ebihara ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Cardiac Function ◽  
Rat Heart ◽  
Diastolic Pressure ◽  
Left Ventricular ◽  
Ventricular Tachyarrhythmias ◽  
Beneficial Effects ◽  
Rat Hearts ◽  
Developed Pressure ◽  
Isolated Rat

The effect of varying the number of preconditioning (PC) episodes on the recovery of cardiac function and on the function of the sarcoplasmic reticulum (SR) was investigated to determine the correlation between the effect of PC and SR function. Isolated rat hearts were subjected to zero to three 5-min episodes of global ischemia with intermittent perfusion (PC0-PC3) followed by 25 min of ischemia (I) and 30 min of reperfusion. The left ventricular (LV) pressure and SR 45Ca2+ uptake in the absence or presence of ryanodine were then measured. The increase in LV end-diastolic pressure and the incidence and duration of ventricular tachyarrhythmias during reperfusion decreased. The recovery of LV developed pressure, LV dP/dtmax and dP/dtmin, increased as the number of episodes of PC increased. The rates of SR 45Ca2+ uptake after PC and after reperfusion were lower in PC3 than in PC0. Conversely, the rate of 45Ca2+ uptake after I did not differ between PC0 and PC3. The ryanodine-sensitive Ca2+ release increased after I, and additional increases were observed during reperfusion in PC0, whereas the release after I and reperfusion decreased progressively in PC3. These observations show that the beneficial effects of PC are associated with a decrease in ryanodine-sensitive SR Ca2+ release.

scholarly journals Long-acting phosphodiesterase-5 inhibitor, tadalafil, induces sustained cardioprotection against lethal ischemic injury

2009 ◽  
Vol 297 (1) ◽  
pp. H387-H391 ◽  
Author(s):  
Nauman Ahmad ◽  
Yigang Wang ◽  
Ailia K. Ali ◽  
Muhammad Ashraf
Keyword(s):  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphodiesterase 5 Inhibitor ◽  
Akt Phosphorylation ◽  
Myocyte Apoptosis ◽  
Long Acting ◽  
Phosphodiesterase 5 ◽  
Phosphatidylinositol 3

The ability of pharmacological preconditioning mimetics to confer long-lasting and sustained cardioprotection may be a logical criterion to develop a drug that can be used clinically for cardioprotection. We propose here that the use of long-acting phosphodiesterase-5 inhibitor, tadalafil, may confer sustained cardioprotection against ischemia. Tadalafil (5 mg/kg) was administered orally to male C57B/6J mice ( n = 6 in each treatment subgroup at each time point studied). Hearts were isolated and subjected to 40 min of ischemia and 30 min of reperfusion on Langendorff's apparatus at 1, 12, 24, 36, 48, 60, 72, and 108 h after tadalafil administration. In 1- to 48-h subgroups, tadalafil was given once at 0 h only. In 60- and 72-h subgroups, tadalafil was given twice at 0 and 36 h. Similarly, in the 108-h subgroup, tadalafil was administered at 0, 36, and 72 h. In the same subgroups, wortmannin (15 μg/kg ip), an inhibitor of phosphatidylinositol 3-kinase or 5-hydroxydecanoic acid (5 mg/kg ip), an inhibitor of mitochondrial ATP-sensitive K+ channels, was given together with tadalafil, and the hearts were subjected to ischemia-reperfusion at 36 h to determine whether the effect of tadalafil on ischemia-reperfusion injury was abolished. As a result, tadalafil treatment reduced left ventricular end-diastolic pressure and increased left ventricular developed pressure as well as reduced lactate dehydrogenase release. This protection remained till 36–40 h, and thereafter it vanished. The readministration of tadalafil at 36 and 72 h restored the protection till 108 h. Tadalafil treatment accelerated Akt phosphorylation in cardiac tissue and decreased myocyte apoptosis. The administration of wortmannin abolished the beneficial effects of tadalafil on hemodynamic parameters and myocyte apoptosis, together with significantly reduced Akt phosphorylation. 5-Hydroxydecanoic acid also abolished the antiapoptotic effect of tadalafil. It is concluded that tadalafil treatment induces the long-term protection of ischemic myocardium via phosphatidylinositol 3-kinase/Akt signaling pathway.

Importance of antioxidant and antiapoptotic effects of β-receptor blockers in heart failure therapy

2004 ◽  
Vol 287 (3) ◽  
pp. H1003-H1012 ◽  
Author(s):  
Keisuke Kawai ◽  
Fuzhong Qin ◽  
Junya Shite ◽  
Weike Mao ◽  
Shuji Fukuoka ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Ventricular Remodeling ◽  
Diastolic Pressure ◽  
Cardiac Pacing ◽  
Left Ventricular ◽  
Beneficial Effects ◽  
Myocyte Apoptosis ◽  
Adrenergic Blocking ◽  
Fractional Shortening

The present study was carried out to determine whether beneficial effects of carvedilol in congestive heart failure (CHF) are mediated via its β-adrenergic blocking, antioxidant, and/or α-adrenergic blocking action. Rabbits with heart failure induced by rapid cardiac pacing were randomized to receive subcutaneous carvedilol, metoprolol, propranolol plus doxazosin, or placebo pellets for 8 wk and compared with sham-operated rabbits without pacing. We found rapid cardiac pacing produced clinical heart failure, left ventricular dilation, and decline of left ventricular fractional shortening. This was associated with an increase in left ventricular end-diastolic pressure, decrease in left ventricular first derivative of left ventricular pressure, and myocyte hypertrophy. Tissue oxidative stress measured by GSH/GSSG was increased in the heart with increased oxidation product of mitochondrial DNA, 8-oxo-7,8-dihydro-2′-deoxyguanosine, increase of Bax, decrease of Bcl-2, and increase of apoptotic myocytes as measured by anti-single-stranded DNA monoclonal antibody. Administration of carvedilol and metoprolol, which had no effect in sham animals, attenuated cardiac ventricular remodeling, cardiac hypertrophy, oxidative stress, and myocyte apoptosis in CHF. In contrast, propranolol plus doxazosin, which has less antioxidant effects, produced smaller effects on left ventricular function and myocyte apoptosis. In all animals, GSH/GSSG correlated significantly with changes of left ventricular end-diastolic dimension ( r = −0.678, P < 0.0001), fractional shortening ( r = 0.706, P < 0.0001), and apoptotic myocytes ( r = −0.473, P = 0.0001). Thus our findings suggest antioxidant and antiapoptotic actions of carvedilol and metoprolol are important determinants of clinical beneficial effects of β-receptors in the treatment of CHF.

Abstract P109: Alteration in Intracellular Calcium During Cardiac Arrest

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Satoshi Takeda ◽  
Hiroshi Yoshida ◽  
Takeki Ogawa
Keyword(s):  
Cardiac Arrest ◽  
Intracellular Calcium ◽  
Cell Injury ◽  
Diastolic Pressure ◽  
Pulseless Electrical Activity ◽  
Left Ventricular Pressure ◽  
Cardiac Metabolism ◽  
Left Ventricular ◽  
Free Calcium ◽  
Developed Pressure

AIM: A cytosolic free calcium is an important regulator of cardiac metabolism and contractility, and an increased [Ca2+]i has been implicated in irreversible cell injury and contractile dysfunction. We investigated intracellular calcium ([Ca2+]i) dynamics during cardiac arrest, especially in pulseless electrical activity (PEA) and asystole. METHODS: Rat hearts (n=18) were perfused with a Langendorff system and loaded with Fura-2/AM, as a [Ca2+]i marker, and BCECF/AM, as a pHi marker. Surface fluorescence of the heart was recorded with an intracellular ion analyzer. A latex balloon was inserted into the left ventricle to monitor left ventricular pressure. Sustained normo-thermic cardiac arrest was induced for 20 min by clamping the aortic cannula. RESULTS: After clamping (cardiac arrest), the left ventricular developed pressure decreased significantly, from 84.3±11 mmHg to 3.88±0.7 mmHg (p<0.01) at 2min. The rhythm was PEA in all cases in this period, followed by asystole. The amplitude of the [Ca2+]i transient (0.30±0.03) was maintained at 2 min, but further significant increases were observed in both systolic (1.14±0.04, p<0.01) and diastolic levels of [Ca2+]i (0.84±0.04, p<0.05), when compared with pre-arrest levels. The [Ca2+]i transient disappeared 4.7±0.6 min. The diastolic [Ca2+]i increased gradually after 5 min to 20 min. This diastolic [Ca2+]i increase was parallel with the increase in left ventricular end diastolic pressure (indicated ischemic contracture). The pHi increased (to 7.6±1.0) immediately after clamping. Thereafter pHi decreased rapidly and remained steady (at pH 6.6±0.6). CONCLUSIONS: The change in the [Ca2+]i-pressure relationship rather than change in the amplitude of the [Ca2+]i transient was the main contributor in the early cardiac arrest phase. The diastolic [Ca2+]i increase might induce irreversible cell injury in the late cardiac arrest phase.

Protective effect of hypoxia on mechanical and metabolic changes induced by hydrogen peroxide in rat hearts

1995 ◽  
Vol 268 (2) ◽  
pp. H614-H620 ◽  
Author(s):  
A. Hara ◽  
Y. Abiko
Keyword(s):  
Hydrogen Peroxide ◽  
Protective Effect ◽  
Receptor Antagonist ◽  
Katp Channel ◽  
Diastolic Pressure ◽  
Left Ventricular ◽  
Metabolic Changes ◽  
Constant Flow Rate ◽  
Adenosine Receptor Antagonist ◽  
Developed Pressure

The effect of hypoxia (20% O2 for 5 min) on the hydrogen peroxide (H2O2)-induced myocardial change was studied in the Langendorff rat heart, which was perfused at a constant flow rate and driven electrically. H2O2 decreased the left ventricular developed pressure, increased the left ventricular end-diastolic pressure, and decreased the myocardial ATP level. These mechanical and metabolic alterations induced by H2O2 were less prominent in the hypoxia-reoxygenated heart than in the normoxic heart (i.e., hypoxia had a protective effect on the H2O2-induced change). Both 8-phenyltheophylline (8-PT), a nonselective adenosine-receptor antagonist, and glyburide (Gly), an inhibitor of the ATP-sensitive potassium (KATP) channel, significantly reduced the protective effect of hypoxia. The adenosine A1-receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DP-CPX) reduced the protective effect of hypoxia incompletely. Gly, 8-PT, and DPCPX did not affect the mechanical function and energy metabolism of the hypoxia-reoxygenated heart without H2O2. These results suggest that brief and mild hypoxia attenuates the H2O2-induced mechanical and metabolic changes and that the protective effect of hypoxia is probably mediated by activation of the adenosine receptors, which open the KATP channel.

Effect of acute edema on left ventricular function and coronary vascular resistance in the isolated rat heart

1994 ◽  
Vol 267 (3) ◽  
pp. H1054-H1061 ◽  
Author(s):  
A. Rubboli ◽  
P. A. Sobotka ◽  
D. E. Euler
Keyword(s):  
Linear Relationship ◽  
Water Content ◽  
Vascular Resistance ◽  
Diastolic Pressure ◽  
Myocardial Edema ◽  
Left Ventricular ◽  
Coronary Vascular Resistance ◽  
Ventricular Performance ◽  
Developed Pressure ◽  
The Impact

The impact of acute myocardial edema on coronary flow and left ventricular performance was studied in isolated isovolumic rat hearts. After 15 min of aortic perfusion with Krebs-Henseleit buffer, hearts (10/group) were either removed for determination of water content or perfused for another 90 min. Three groups were perfused at a constant pressure of 60, 100, or 140 mmHg, and two groups were perfused at 60 or 140 mmHg with adenosine added. Compared with the 15-min group, there was a significant increase in water content in all groups except the 60-mmHg group (P < 0.005). There was a direct linear relationship between increases in coronary vascular resistance over time and water content (P < 0.0001). A decrease in developed pressure and peak +dP/dt was observed only in those groups that accumulated water. An inverse linear relationship was found between changes in developed pressure and water content (P = 0.0001). Water content had no effect on end-diastolic pressure below 5 ml/g; above 5 ml/g, a direct linear relationship was evident (P = 0.009). The results suggest that myocardial edema increases vascular resistance and decreases systolic performance. End-diastolic pressure is less influenced by edema than either systolic or coronary vascular function.

scholarly journals Mitochondrial transplantation for myocardial protection in diabetic hearts

2019 ◽  
Vol 57 (5) ◽  
pp. 836-845 ◽  
Author(s):  
Ilias P Doulamis ◽  
Alvise Guariento ◽  
Thomas Duignan ◽  
Arzoo Orfany ◽  
Takashi Kido ◽  
...  
Keyword(s):  
Diastolic Pressure ◽  
Ex Vivo ◽  
Left Ventricular ◽  
Diabetic Rat ◽  
Ischaemia Reperfusion Injury ◽  
Global Ischaemia ◽  
Aortic Cannula ◽  
Developed Pressure ◽  
Perfused Hearts

Abstract OBJECTIVES Type 2 diabetes causes mitochondrial dysfunction, which increases myocardial susceptibility to ischaemia–reperfusion injury. We investigated the efficacy of transplantation of mitochondria isolated from diabetic or non-diabetic donors in providing cardioprotection from warm global ischaemia and reperfusion in the diabetic rat heart. METHODS Ex vivo perfused hearts from Zucker diabetic fatty (ZDF fa/fa) rats (n = 6 per group) were subjected to 30 min of warm global ischaemia and 120 min reperfusion. Immediately prior to reperfusion, vehicle alone (VEH) or vehicle containing mitochondria isolated from either ZDF (MTZDF) or non-diabetic Zucker lean (ZL +/?) (MTZL) skeletal muscle were delivered to the coronary arteries via the aortic cannula. RESULTS Following 30-min global ischaemia and 120-min reperfusion, left ventricular developed pressure was significantly increased in MTZDF and MTZL groups compared to VEH group (MTZDF: 92.8 ± 5.2 mmHg vs MTZL: 110.7 ± 2.4 mmHg vs VEH: 44.3 ± 5.9 mmHg; P &lt; 0.01 each); and left ventricular end-diastolic pressure was significantly decreased (MTZDF 12.1 ± 1.3 mmHg vs MTZL 8.6 ± 0.8 mmHg vs VEH: 18.6 ± 1.5 mmHg; P = 0.016 for MTZDF vs VEH and P &lt; 0.01 for MTZL vs VEH). Total tissue ATP content was significantly increased in both MT groups compared to VEH group (MTZDF: 18.9 ± 1.5 mmol/mg protein/mg tissue vs MTZL: 28.1 ± 2.3 mmol/mg protein/mg tissue vs VEH: 13.1 ± 0.5 mmol/mg protein/mg tissue; P = 0.018 for MTZDF vs VEH and P &lt; 0.01 for MTZL vs VEH). Infarct size was significantly decreased in the MT groups (MTZDF: 11.8 ± 0.7% vs MTZL: 9.9 ± 0.5% vs VEH: 52.0 ± 1.4%; P &lt; 0.01 each). CONCLUSIONS Mitochondrial transplantation significantly enhances post-ischaemic myocardial functional recovery and significantly decreases myocellular injury in the diabetic heart.

Inhibition of the creatine kinase reaction decreases the contractile reserve of isolated rat hearts

1995 ◽  
Vol 269 (3) ◽  
pp. H1030-H1036 ◽  
Author(s):  
B. L. Hamman ◽  
J. A. Bittl ◽  
W. E. Jacobus ◽  
P. D. Allen ◽  
R. S. Spencer ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Dynamic Range ◽  
Acute Stress ◽  
Diastolic Pressure ◽  
Left Ventricular ◽  
Stress Conditions ◽  
Contractile Reserve ◽  
Phosphoryl Transfer ◽  
Rat Hearts ◽  
Developed Pressure

To define the relation between phosphoryl transfer via creatine kinase (CK) and the ability of the intact beating heart to do work, we chemically inhibited CK activity and then measured cardiac performance under physiological and acute stress conditions. Isolated perfused rat hearts were exposed to iodoacetamide (IA) and subjected to one of three cardiac stresses: hypercalcemic (Ca2+ = 3 mM) buffer perfusion (n = 7), norepinephrine (2 mumol/min) infusion (n = 6), or hypoxic buffer perfusion (n = 5). IA decreased CK activity to near zero, measured in intact hearts by 31P magnetization transfer, and to 2% of control CK activity, measured in myocardial homogenates. The CK isoenzyme profile was unchanged, suggesting nonselective IA inhibition of all isoenzymes. Mitochondria isolated from IA-treated hearts had normal ADP:O ratios, state 3 respiratory rates, and unchanged acceptor and respiratory control ratios. Neither actomyosin adenosinetriphosphatase nor adenylate kinase activities were changed. After IA exposure, end-diastolic pressure, left ventricular developed pressure, and heart rate were unchanged for at least 30 min at physiological perfusion pressures, but large changes were observed during stress conditions. The increase in left ventricular developed pressure induced by hypercalcemic perfusion and by norepinephrine infusion decreased by 39 and 54%, respectively. During hypoxia, the rate of phosphocreatine depletion was decreased by 57%, left ventricular developed pressure declined, and end-diastolic pressure increased faster than in controls. These results show that inhibition of CK to < 2% of control activity by IA reduced contractile reserve by approximately 50%. We conclude that CK activity is essential for the expression of the full dynamic range of myocardial performance.

Role of oxidative stress in alterations of mitochondrial function in ischemic-reperfused hearts

2007 ◽  
Vol 292 (4) ◽  
pp. H1986-H1994 ◽  
Author(s):  
Zhanna Makazan ◽  
Harjot K. Saini ◽  
Naranjan S. Dhalla
Keyword(s):  
Oxidative Stress ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Respiratory Control ◽  
Left Ventricular ◽  
Cardiac Performance ◽  
Developed Pressure

To study the mechanisms of mitochondrial dysfunction due to ischemia-reperfusion (I/R) injury, rat hearts were subjected to 20 or 30 min of global ischemia followed by 30 min of reperfusion. After recording both left ventricular developed pressure (LVDP) and end-diastolic pressure (LVEDP) to monitor the status of cardiac performance, mitochondria from these hearts were isolated to determine respiratory and oxidative phosphorylation activities. Although hearts subjected to 20 min of ischemia failed to generate LVDP and showed a marked increase in LVEDP, no changes in mitochondrial respiration and phosphorylation were observed. Reperfusion of 20-min ischemic hearts depressed mitochondrial function significantly but recovered LVDP completely and lowered the elevated LVEDP. On the other hand, depressed LVDP and elevated LVEDP in 30-min ischemic hearts were associated with depressions in both mitochondrial respiration and oxidative phosphorylation. Reperfusion of 30-min ischemic hearts elevated LVEDP, attenuated LVDP, and decreased mitochondrial state 3 and uncoupled respiration, respiratory control index, ADP-to-O ratio, as well as oxidative phosphorylation rate. Alterations of cardiac performance and mitochondrial function in I/R hearts were attenuated or prevented by pretreatment with oxyradical scavenging mixture (superoxide dismutase and catalase) or antioxidants [ N-acetyl-l-cysteine or N-(2-mercaptopropionyl)-glycine]. Furthermore, alterations in cardiac performance and mitochondrial function due to I/R were simulated by an oxyradical-generating system (xanthine plus xanthine oxidase) and an oxidant (H2O2) either upon perfusing the heart or upon incubation with mitochondria. These results support the view that oxidative stress plays an important role in inducing changes in cardiac performance and mitochondrial function due to I/R.

Deleterious effect of ouabain on myocardial function during hypoxia

1989 ◽  
Vol 256 (3) ◽  
pp. H681-H687
Author(s):  
M. J. Cunningham ◽  
C. S. Apstein ◽  
E. O. Weinberg ◽  
B. H. Lorell
Keyword(s):  
Myocardial Function ◽  
Diastolic Pressure ◽  
Lactate Production ◽  
Treated Group ◽  
Left Ventricular ◽  
Ventricular Performance ◽  
Fiber Tension ◽  
Coronary Vasodilatation ◽  
Developed Pressure ◽  
Ventricular Distensibility

The effect of cardiac glycosides on myocardial function during hypoxia is controversial. Accordingly, we studied left ventricular performance during hypoxia and reoxygenation in the presence of a mildly inotropic, nontoxic dose of ouabain using isolated, isovolumic, buffer-perfused rabbit hearts. After 15 min of hypoxia, left ventricular developed pressure was less in the ouabain-treated group than in controls (35 +/- 4 vs. 55 +/- 3 mmHg, P less than 0.025). Left ventricular end-diastolic pressure (LVEDP) increased more during hypoxia in the presence of ouabain (9 +/- 1 to 32 +/- 7 with ouabain vs. 9 +/- 1 to 14 +/- 3 mmHg without ouabain, P less than 0.005) despite comparable degrees of coronary vasodilatation and myocardial lactate production in the two groups. When coronary flow was abruptly reduced to zero to eliminate the coronary turgor contribution to diastolic pressure, LVEDP after 15 min of hypoxia in the presence of ouabain was greater than that in control hearts that did not receive ouabain (13 +/- 4 vs. 4 +/- 1 mmHg, P less than 0.05), implicating greater diastolic myocardial fiber tension in the ouabain group during hypoxia. With reoxygenation, recovery of developed pressure was less and end-diastolic pressure remained elevated in the ouabain-treated group when compared with controls. We conclude that a modestly inotropic dose of ouabain exacerbates the decrease in diastolic ventricular distensibility induced by hypoxia, worsens the decline in developed pressure during hypoxia, and impairs recovery during reoxygenation.

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